Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies

Abstract

It is now a decade since human induced pluripotent stem cells (hiPSCs) were first described. The reprogramming of adult somatic cells to a pluripotent state has become a robust technology that has revolutionised our ability to study human diseases. Crucially, these cells capture all the genetic aspects of the patient from which they were derived. Combined with advances in generating the different cell types present in the human heart, this has opened up new avenues to study cardiac disease in humans and investigate novel therapeutic approaches to treat these pathologies. Here, we provide an overview of the current state of the field regarding the generation of cardiomyocytes from human pluripotent stem cells and methods to assess them functionally, an essential requirement when investigating disease and therapeutic outcomes. We critically evaluate whether treatments suggested by these in vitro models could be translated to clinical practice. Finally, we consider current shortcomings of these models and propose methods by which they could be further improved.

Keywords: Cardiac arrhythmia; Cardiometabolic disease; Cardiomyopathy; Disease model; Genetic cardiac disease; Pluripotent stem cell; hiPSC.

Fig. 1.

Examples of phenotypic properties that can be quantitatively assessed in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). Human iPSCs, generated by reprogramming adult somatic cells, or ESCs isolated from human blastocysts, can be differentiated into cardiomyocytes using small molecules, cytokines or a combination of both. The resulting cardiomyocytes can then be used in downstream assays to measure their contractility, electrophysiology, Ca²⁺ flux, mitochondrial function or morphology. If the hPSC-CMs contain genetic mutations associated with cardiac disease, this can provide insight into the underlying disease mechanisms and also enable new therapeutic strategies to be evaluated.

Fig. 2.

Overview of congenital cardiac diseases that have been modelled using hPSC-CMs. The main cellular sublocalisation of the protein affected in each disease is indicated. The diseases caused by defects in each protein are shown in brackets. A more extensive list of the mutations that have been examined is provided in Table 2. ACM, arrhythmogenic cardiomyopathy; ALDH, aldehyde dehydrogenase; BrS, Brugada syndrome; BTHS, Barth syndrome; LTCC, L-type calcium channel; CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; FD, Fabry disease; HCM, hypertrophic cardiomyopathy; JLNS, Jervell and Lange-Nielsen syndrome; LQT, long QT syndrome; K_v7.1, voltage-gated, slow rectifier potassium channel; K_v11.1, voltage-gated, fast rectifier potassium channel; Na_v1.5, voltage-gated cardiac sodium channel; NCX, sodium/calcium exchanger; NKA, sodium/potassium exchanger; SR, sarcoplasmic reticulum.